Anesthesiologists have long recognized the need to reduce the dose of intravenous anesthetic for patients who suffer significant blood loss before or during surgery. The scientific foundation upon which to base rational dosing regimens, however, does not exist. In the setting of hemorrhagic shock, intravenous agents can produce adverse hemodynamic consequences and prolonged duration of anesthetic effect. The absence of a scientific foundation to guide the rational selection and administration of intravenous anesthetics during shock represents a huge gap in the anesthesia clinical pharmacology literature. The goal of this grant is to investigate the influence of hemorrhagic shock and fluid resuscitation on the pharmacokinetic and pharmacodynamic properties of a short and long acting opioid, neuromuscular blocker, and sedative-hypnotic. The specific aims of this proposal are to characterize the influence of hemorrhagic shock and crystalloid resuscitation after hemorrhagic shock on the pharmacokinetic and pharmacodynamic profile of intravenously administered opioids, muscle relaxants, and sedative hypnotics. With this data, combined pharmacokinetic/pharmacodynamic models for each agent studied under normotensive, shocked, and resuscitated conditions will serve as a tool to explore how dosing can be adjusted to optimize the desired effect while minimizing the adverse consequences of over or under dosing. The principal investigator has had preliminary research experience in the areas of pharmacokinetic and pharmacodynamic analysis and the pathophysiology of hemorrhagic shock. The principal investigator has selected a mentor with (i) extensive research training in clinical pharmacology and (ii) a willingness to dedicate time and resources to ensure appropriate clinical research training. This grant will enable the principal investigator to expand his expertise in high resolution pharmacokinetic/ pharmacodynamic analysis and apply it to the study of how hemorrhagic shock influences the clinical pharmacology of intravenous anesthetics. Career development associated with this grant will include presenting results at national meetings, submission of results to peer reviewed journals for publication, and participation in courses and workshops related to the proposed study. The proposed studies will be carried out in the Department of Anesthesiology at the University of Utah which include an AAALAC accredited animal laboratory and animal housing facility. The principal investigator's long term career goals include: (i) develop collaborations with other investigators outside the University of Utah to enhance the work performed under this grant and future work and (ii) develop expertise and experimental methods needed to establish a laboratory capable of attracting future funding in areas pertinent to anesthesia and trauma care.